The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib
| Autor: | Karthick, Vishwanathan, Paul A, Dickinson, Karen, So, Karen, Thomas, Yuh-Min, Chen, Javier, De Castro Carpeño, Anne-Marie C, Dingemans, Hye Ryun, Kim, Joo-Hang, Kim, Matthew G, Krebs, James, Chih-Hsin Yang, Khanh, Bui, Doris, Weilert, R Donald, Harvey |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
Male Lung Neoplasms Administration Oral Antineoplastic Agents Models Biological Risk Assessment Drug Administration Schedule Piperazines Risk Factors Carcinoma Non-Small-Cell Lung Humans Drug Interactions Protein Kinase Inhibitors Aged Aged 80 and over Acrylamides Aniline Compounds Cytochrome P-450 CYP3A Inducers Original Articles Middle Aged Treatment Outcome Cytochrome P-450 CYP3A Inhibitors Female Itraconazole Rifampin |
| Zdroj: | British journal of clinical pharmacology. 84(6) |
| ISSN: | 1365-2125 |
| Popis: | AIMS: We investigated the effects of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampicin) on the pharmacokinetics of the epidermal growth factor receptor‐tyrosine kinase inhibitor osimertinib, in patients with advanced non‐small cell lung cancer in two Phase I, open‐label, two‐part clinical studies. Part one of both studies is reported. METHODS: In the itraconazole study (NCT02157883), patients received single‐dose osimertinib 80 mg on Days 1 and 10 and itraconazole (200 mg twice daily) on Days 6–18 orally. In the rifampicin study (NCT02197247), patients received osimertinib 80 mg once daily on Days 1–77 and rifampicin 600 mg once daily on Days 29–49. RESULTS: In the itraconazole study (n = 36), the geometric least squares mean (GMLSM) ratios (osimertinib plus itraconazole/osimertinib alone) for C (max) and AUC were 80% (90% CI 73, 87) and 124% (90% CI 115, 135), respectively, below the predefined no‐effect upper limit of 200%. In the rifampicin study (n = 40), the GMLSM ratios (osimertinib plus rifampicin/osimertinib alone) for C (ss,max) and AUCτ were 27% (90% CI 24, 30) and 22% (90% CI 20, 24), respectively, below the predefined no‐effect lower limit of 50%. The induction effect of rifampicin was apparent within 7 days of initiation; osimertinib C (ss,max) and AUCτ values returned to pre‐rifampicin levels within 3 weeks of rifampicin discontinuation. No new osimertinib safety findings were observed. CONCLUSIONS: Osimertinib can be co‐administered with CYP3A4 inhibitors, but strong CYP3A inducers should be avoided if possible. |
| Databáze: | OpenAIRE |
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